Rethinking CNS drug discovery: What can we learn from successes in oncology? guest post by Hamish McDougall with commentary

Today we have another guest post from UK-based Hamish McDougall, a knowledgable analysis of the Alzheimer’s drug development space and all around pleasant chap. I felt a few introductory comments were warranted.

The comparison between cancer (uncontrolled cell growth) and “Alzheimer’s” (uncontrolled cell death) is apt. Some have hypothesized defects in the same biological pathways like cell cycle regulation. Cancer also shows us some of important questions to ask relevant to dementia. What is cancer? Is all cell dysplasia cancer? Why do cancers increase with age? Why does early diagnosis not always improve outcomes? Why do cancer drugs cost so much (doctor and pharma profiteering)? How can we afford to develop drugs for very small numbers of specific type of cancers? Is there one common mechanism to all cancers waiting to be found?

Hamish is optimistic about the future of drugs for dementia if we learn some lessons from cancer. I (Peter) am less so. I think so-called late onset so-called Alzheimer’s involves many different processes in different people. The brain is a very challenging organ to influence positively biologically. Finally, I think, just as in cancer, if we do not attend to environmental, economic, and social determinants of health.

Rethinking CNS drug discovery: What can we learn from successes in oncology?

by Hamish McDougall

Drug development for disorders of the central nervous system (CNS) has never seemed like a less attractive prospect. One by one big pharmaceutical companies pull out of CNS research, selling off their assets whilst cutting jobs. It’s almost difficult to remember a time when CNS research and drug development dominated the pharmaceutical industry, however, changes in the process of drug discovery coupled with a generally poor understanding of the biology of CNS disorders is severely hindering progress.

In an age where serendipity is no longer the holy grail of drug discovery it’s crucial to learn what we can from successful targeted innovation. Many question whether the increased funding and effort in oncology has been worth it but with the advent of immuno-oncology and a number of approvals in the last five years I would argue that it has been an resounding success. Those working in CNS, should be look to cancer research as the model of drug discovery success.

Understanding the basics

Tumour biology is certainly no walk in the park but it pales in comparison to the complexity of the brain. But whilst CNS drug discovery stagnates with only a handful of noteworthy drug candidates in the pipeline, oncology is on the cusp of a revolution thanks to the work done to understand how exactly the tumour is able to evade our own immune system.
Though it is still early days, some drugs are already beginning to hit the market and it has spurred a renewed interest in the idea of “Immuno-oncology” (IO). Harnessing the immune system against cancer is a very old idea dating back to the late 1800s, however only understanding the relationship between tumours and the immune system has allowed the development of drugs to harness our body’s natural defences.

What is particularly encouraging is that this research has spawned not only a few drugs, but an entire concept, a notion of how to achieve effective long-term control over a range of devastating diseases and now new drugs targeting other aspects of the immune system are also in early testing.

Though IO is certainly not a cure and it does not work in everyone, this is one of the greatest advances in modern medicine and this year’s American Society of Clinical Oncology (ASCO) annual meeting was rife with exciting results bound to lead to further drug approvals.

In CNS, like the earliest days of IO, we are certainly not short of ideas of how to target diseases. However, we lack the basic understanding of the biology of the CNS that would allow us to actually make these ideas work.

Will one drug ever be enough?

Diseases like Alzheimer’s and Parkinson’s have classically been approached by either looking symptomatically or targeting one pathology in the disease such as protein clusters. However, it’s becoming increasingly obvious that no one single facet can drive the entire disease and that either multiple drugs are necessary or a drug capable of targeting multiple pathologies is necessary.

In Alzheimer’s disease researchers have long argued whether one pathology is more important than another. We have been obsessed with the amyloid-beta protein whilst totally neglecting the role of tau. Whether amyloid-beta or tau is more important for disease progression seems rather an irrelevant point when both pathologies exist, surely it is time to look at both.

We might even need to use multiple treatments to target one pathology. We have long focused on immunotherapies for removal of amyloid-beta in Alzheimer’s disease, but say that these treatments work, we may also want to look at combining these drugs with a treatment targeting some of the downstream events that lead to the production of the protein to maximise on efficacy.

In oncology combination therapy is the norm, for example various chemotherapies are combined to maximise efficacy and each time a new drug is discovered its effect with chemotherapy is usually high priority for investigation.

Aforementioned IO is under investigation with pretty much any classic or targeted therapy in existence. Oncologists even use combination therapies to ameliorate the side effects of aggressive treatments that cannot be tolerated. For example there is an entire field of research dedicated to controlling nausea and vomiting after chemotherapy. Some might argue that it is not ideal to treat so aggressively and cause such side effects but when you are battling an aggressive disease you must be pragmatic in your approach and willing to compromise.

Genetic drivers should not be ignored

Oncologists have long abandoned the idea of discrete categories of diseases. Lung cancer can be divided into small-cell lung cancer or non-small-cell lung cancer (NSCLC). NSCLC can be further sub divided a number of distinct diseases. From there genetic factors become important and sub-categories can be subdivided by their genetic drivers, if they exist. The divisions and sub divisions keep on appearing which spurs innovation to target the root cause of the issue in these sub-populations of patients.

In Alzheimer’s disease we have done countless Genome Wide Association Studies (GWAS) and yet we continue to ignore the role of the Apo-E4 gene. A gene that clearly plays such an important role in the disease deserves far more attention. However, there are other genes of interest in Alzheimer’s disease and these deserve proper study too.

Trial design is key

This links back in with the last point, and as long as we continue to use broad classifications CNS clinical trials will face the same extraordinarily high failure rates. In Alzheimer’s disease clearly patients are very heterogeneous and to consider everyone’s disease as the same is a critical error.

One of the greatest successes of the recent Biogen trial was to screen patients for the presence of the amyloid-beta protein. It makes clear sense to make sure patients have the pathology that you are trying to treat with a drug.

However, there are many patients with what we classically consider Alzheimer’s disease that would not have been allowed to take part in that trial as they would have screened negative for amyloid-beta. At some level disease classification becomes rather irrelevant in clinical trials, and what is crucial is selecting the population that can benefit from your drug. What is the point of having a drug that targets tau tangles in Alzheimer’s patients if you are administering it to patients that do not suffer this problem?

As long as we continue with our nebulous ideas about CNS disease pathology, new drug treatments will continue to evade us. Using the example of lung cancer once again, when gefitinib and erlotinib first were first being tested, they were largely disappointing as patients used in early clinical trials were so heterogeneous. The discovery of a small subgroup of patients deriving extraordinary benefit from lead to the discovery of epidermal growth factor receptor driven NSCLC and allowed oncologists to design trials targeted to those patients that would receive the most benefit.

In Parkinson’s disease we badly need biomarkers otherwise we will not be able to select out the patients that may be able to benefit from new and exciting early stage treatments. Parkinson’s disease patients are highly variable and 20% of patients first diagnosed with the condition turn out to have a different disorder or atypical Parkinsonism.

Maybe so many of our failed CNS drugs were just not targeting the correct patients. Thankfully this point is now recognised as a serious issue and trial design is certainly getting better, but there is still significant room for improvement.

Time and money reaps rewards

The greatest thing for oncology innovation was the investment of time and money. Though for years it seemed like there was very little progress ultimately the rewards are now being seen. Now that diseases such as Alzheimer’s disease are starting to get the recognition they deserve we must hope that continued investment will lead towards the same sort of advances that have been seen in the field of oncology.

Peter J. Whitehouse, MD, PhD is Professor of Neurology and former Professor of Psychiatry, Neuroscience, Psychology, Nursing, Organizational Behavior, Cognitive Science, Bioethics and History. He is an intergenerative, narrative-focused evolutionary physician and health coach. His main passion is developing innovative learning environments (such as The Intergenerational School) to promote collective wisdom and contribute to individual, community, and planetary health.